Bottom Line:
They can express and secrete pro-inflammatory cytokines and therefore trigger prolonged inflammation, resulting in neurodegeneration.Microglial cells express and release a wide range of inflammation-associated molecules including several components of the complement system.Astrocytes express β-defensins, which can chemoattract and promote maturation of dendritic cells (DC), and can also limit inflammation by controlling the viability of these same DC.

Affiliation: Perinatal Brain Repair Group, Department of Maternal and Fetal Medicine, Institute for Women's Health, University College London , London , UK.

ABSTRACTHypoxic-ischemic encephalopathy (HIE) is a clinical condition in the neonate, resulting from oxygen deprivation around the time of birth. HIE affects 1-5/1000 live births worldwide and is associated with the development of neurological deficits, including cerebral palsy, epilepsy, and cognitive disabilities. Even though the brain is considered as an immune-privileged site, it has innate and adaptive immune response and can produce complement (C) components and antimicrobial peptides (AMPs). Dysregulation of cerebral expression of AMPs and C can exacerbate or ameliorate the inflammatory response within the brain. Brain ischemia triggers a prolonged inflammatory response affecting the progression of injury and secondary energy failure and involves both innate and adaptive immune systems, including immune-competent and non-competent cells. Following injury to the central nervous system (CNS), including neonatal hypoxia-ischemia (HI), resident microglia, and astroglia are the main cells providing immune defense to the brain in a stimulus-dependent manner. They can express and secrete pro-inflammatory cytokines and therefore trigger prolonged inflammation, resulting in neurodegeneration. Microglial cells express and release a wide range of inflammation-associated molecules including several components of the complement system. Complement activation following neonatal HI injury has been reported to contribute to neurodegeneration. Astrocytes can significantly affect the immune response of the CNS under pathological conditions through production and release of pro-inflammatory cytokines and immunomodulatory AMPs. Astrocytes express β-defensins, which can chemoattract and promote maturation of dendritic cells (DC), and can also limit inflammation by controlling the viability of these same DC. This review will focus on the balance of complement components and AMPs within the CNS following neonatal HI injury and the effect of that balance on the subsequent brain damage.

Figure 2: Activation of the complement cascade. Activation of all three C pathways generates homologous variants of C3-convertase cleaving C3 into C3a and C3b, whereas C3a stimulates mast cell degranulation and has chemotactic properties, and C3b acts as an opsonin and binds to the surface of pathogens. Increasing C3b deposition leads to the formation of C5-convertases cleaving C5 into the chemotactic C5a, and the fragment C5b, which together with C6, C7, C8, and the polymeric C9 forms the membrane attack complex (MAC) leading to the formation of transmembrane channel and osmotic lysis of the targeted pathogen. The classical pathway (CP) is initiated by binding of the C1-complex, consisting of a C1q molecule and a tetramer of 2 C1r and 2 C1s molecules, to antigen-bound IgM or IgG. The C1-complex cleaves C2 and C4 into C2a and C2b, and C4a and C4b, respectively. The C2a and C4b fragments form the CP C3-convertase. The lectin pathway activation is due to binding of mannose-binding lectin (MBL) and ficolins (Ficolin-1, -2, and -3) to carbohydrate pattern on microorganisms and dying cells, thus activating the MBL-associated serine proteases MASP-1 and MASP-2, which would in turn cleave C2 and C4. The alternative pathway (AP) is continuously activated through spontaneous C3-hydrolysis, resulting in formation of C3 convertases, which cleave C3 to a C3b-like C3, i.e., C3(H2O). Complement regulators are typically present on host cells and absent on pathogens, thus allowing C3(H2O) to bind factor B on the surface of the latter, and form additional C3 convertases after activation by factor D. In the presence of Factor D, C3(H2O)B is cleaved to Ba and Bb and forms C3(H2O)Bb, which in turn cleaves C3 to C3a and C3b forming C3bBb, which is stabilized by properdin. Properdin bound to microbial surfaces and apoptotic and/or necrotic cells can recruit C3 and also activate the AP (82). The final C3bBbP complex enzymatically cleaves more C3 and amplifies C activation. The C3-convertase of the AP can bind another C3b fragment and the resulting complex C3bBbP(C3b)n acts as a C5-convertase and triggers the formation of MAC and pathogen elimination.

Mentions:
The complement system consists of more than 30 soluble and cell-associated factors and can be activated through three pathways (classical, alternative, and lectin) (Figure 2). The components of the complement system are synthesized to a great extent not only by hepatocytes but also by tissue macrophages, blood monocytes, and epithelial cells of the gastrointestinal and genitourinary tracts.

Figure 2: Activation of the complement cascade. Activation of all three C pathways generates homologous variants of C3-convertase cleaving C3 into C3a and C3b, whereas C3a stimulates mast cell degranulation and has chemotactic properties, and C3b acts as an opsonin and binds to the surface of pathogens. Increasing C3b deposition leads to the formation of C5-convertases cleaving C5 into the chemotactic C5a, and the fragment C5b, which together with C6, C7, C8, and the polymeric C9 forms the membrane attack complex (MAC) leading to the formation of transmembrane channel and osmotic lysis of the targeted pathogen. The classical pathway (CP) is initiated by binding of the C1-complex, consisting of a C1q molecule and a tetramer of 2 C1r and 2 C1s molecules, to antigen-bound IgM or IgG. The C1-complex cleaves C2 and C4 into C2a and C2b, and C4a and C4b, respectively. The C2a and C4b fragments form the CP C3-convertase. The lectin pathway activation is due to binding of mannose-binding lectin (MBL) and ficolins (Ficolin-1, -2, and -3) to carbohydrate pattern on microorganisms and dying cells, thus activating the MBL-associated serine proteases MASP-1 and MASP-2, which would in turn cleave C2 and C4. The alternative pathway (AP) is continuously activated through spontaneous C3-hydrolysis, resulting in formation of C3 convertases, which cleave C3 to a C3b-like C3, i.e., C3(H2O). Complement regulators are typically present on host cells and absent on pathogens, thus allowing C3(H2O) to bind factor B on the surface of the latter, and form additional C3 convertases after activation by factor D. In the presence of Factor D, C3(H2O)B is cleaved to Ba and Bb and forms C3(H2O)Bb, which in turn cleaves C3 to C3a and C3b forming C3bBb, which is stabilized by properdin. Properdin bound to microbial surfaces and apoptotic and/or necrotic cells can recruit C3 and also activate the AP (82). The final C3bBbP complex enzymatically cleaves more C3 and amplifies C activation. The C3-convertase of the AP can bind another C3b fragment and the resulting complex C3bBbP(C3b)n acts as a C5-convertase and triggers the formation of MAC and pathogen elimination.

Mentions:
The complement system consists of more than 30 soluble and cell-associated factors and can be activated through three pathways (classical, alternative, and lectin) (Figure 2). The components of the complement system are synthesized to a great extent not only by hepatocytes but also by tissue macrophages, blood monocytes, and epithelial cells of the gastrointestinal and genitourinary tracts.

Bottom Line:
They can express and secrete pro-inflammatory cytokines and therefore trigger prolonged inflammation, resulting in neurodegeneration.Microglial cells express and release a wide range of inflammation-associated molecules including several components of the complement system.Astrocytes express β-defensins, which can chemoattract and promote maturation of dendritic cells (DC), and can also limit inflammation by controlling the viability of these same DC.

Affiliation:
Perinatal Brain Repair Group, Department of Maternal and Fetal Medicine, Institute for Women's Health, University College London , London , UK.

ABSTRACTHypoxic-ischemic encephalopathy (HIE) is a clinical condition in the neonate, resulting from oxygen deprivation around the time of birth. HIE affects 1-5/1000 live births worldwide and is associated with the development of neurological deficits, including cerebral palsy, epilepsy, and cognitive disabilities. Even though the brain is considered as an immune-privileged site, it has innate and adaptive immune response and can produce complement (C) components and antimicrobial peptides (AMPs). Dysregulation of cerebral expression of AMPs and C can exacerbate or ameliorate the inflammatory response within the brain. Brain ischemia triggers a prolonged inflammatory response affecting the progression of injury and secondary energy failure and involves both innate and adaptive immune systems, including immune-competent and non-competent cells. Following injury to the central nervous system (CNS), including neonatal hypoxia-ischemia (HI), resident microglia, and astroglia are the main cells providing immune defense to the brain in a stimulus-dependent manner. They can express and secrete pro-inflammatory cytokines and therefore trigger prolonged inflammation, resulting in neurodegeneration. Microglial cells express and release a wide range of inflammation-associated molecules including several components of the complement system. Complement activation following neonatal HI injury has been reported to contribute to neurodegeneration. Astrocytes can significantly affect the immune response of the CNS under pathological conditions through production and release of pro-inflammatory cytokines and immunomodulatory AMPs. Astrocytes express β-defensins, which can chemoattract and promote maturation of dendritic cells (DC), and can also limit inflammation by controlling the viability of these same DC. This review will focus on the balance of complement components and AMPs within the CNS following neonatal HI injury and the effect of that balance on the subsequent brain damage.